Diane H. Song

Glucose-Dependent Insulinotropic Polypeptide Modulates Adipocyte Lipolysis and Reesterification

Objective: Glucose‐dependent insulinotropic polypeptide (GIP) is an incretin released from intestinal K‐cells during the postprandial period. Previous studies have suggested that GIP may play an etiologic role in obesity; thus, the GIP receptor may represent a target for anti‐obesity drugs. The present studies were conducted to elucidate mechanisms by which GIP might promote obesity by examining the effect of GIP on both glycerol release (indicative of lipolysis) and free fatty acid (FFA) release (indicative of both lipolysis and reesterification), as well as the ability of a GIP‐specific receptor antagonist (ANTGIP) to attenuate these effects.

COX-2 selective inhibition reverses the trophic properties of gastrin in colorectal cancer

Gastrin is a gastrointestinal peptide that possesses potent trophic properties on both normal and neoplastic cells of gastrointestinal origin. Previous studies have indicated that chronic hypergastrinaemia increases the risk of colorectal cancer and cancer growth and that interruption of the effects of gastrin could be a potential target in the treatment of colorectal cancer. Here we demonstrate that gastrin leads to a dose-dependent increase in colon cancer cell proliferation and tumour growth in vitro and in vivo, and that this increment is progressively reversed by pretreatment with the cyclo-oxygenase-2 inhibitor NS-398. Gastrin was able to induce cyclo-oxygenase-2 protein expression, as well as the synthesis of prostaglandin E2, the major product of cyclo-oxygenase. Moreover, gastrin leads to approximately a two-fold induction of cyclo-oxygenase-2 promoter activity in transiently transfected cells. The results of these studies demonstrate that cyclo-oxygenase-2 appears to represent one of the downstream targets of gastrin and that selective cyclo-oxygenase-2 inhibition is capable of reversing the trophic properties of gastrin and presumably might prevent the growth of colorectal cancer induced by hypergastrinaemia.

Attenuation of Peroxisome Proliferator-activated Receptor γ (PPARγ) Mediates Gastrin-stimulated Colorectal Cancer Cell Proliferation

Peroxisome proliferators-activated receptor γ (PPARγ) has been shown to suppress cell proliferation and tumorigenesis, whereas the gastrointestinal regulatory peptide gastrin stimulates the growth of neoplastic cells. The present studies were directed to determine whether changes in PPARγ expression might mediate the effects of gastrin on the proliferation of colorectal cancer (CRC). Initially, using growth assays, we determined that the human CRC cell line DLD-1 expressed both functional PPARγ and gastrin receptors. Amidated gastrin (G-17) attenuated the growth suppressing effects of PPARγ by decreasing PPARγ activity and total protein expression, in part through an increase in the rate of proteasomal degradation. G-17-induced degradation of PPARγ appeared to be mediated through phosphorylation of PPARγ at serine 84 by a process involving the biphasic phosphorylation of ERK1/2 and activation of the epidermal growth factor receptor (EGFR). These results were confirmed through the use of EGFR antagonist AG1478 and MEK1 inhibitor PD98059. Furthermore, mutation of PPARγ at serine 84 reduced the effects of G-17, as evident by inability of G-17 to attenuate PPARγ promoter activity, degrade PPARγ, or inhibit the growth suppressing effects of PPARγ. The results of these studies demonstrate that the trophic properties of gastrin in CRC may be mediated in part by transactivation of the EGFR and phosphorylation of ERK1/2, leading to degradation of PPARγ protein and a decrease in PPARγ activation.

Glucose-dependent insulinotropic polypeptide and its role in obesity.

Purpose of reviewAs we strive to improve our understanding of the factors that contribute to the pathogenesis of obesity, it is certainly logical to speculate that a nutrition-dependent component emanating from the gastrointestinal tract, which has the capacity to regulate insulin expression, could represent an etiologic factor in this serious health issue. One such regulatory peptide that possesses these properties is glucose-dependent insulinotropic polypeptide. Release of this peptide is stimulated by the ingestion of glucose and fat from the upper portion of the small intestine, which in turn enhances the release of insulin from the pancreas. Recent findingsIn addition to its indirect effects in inducing obesity through the stimulation of insulin, a potent efficiency hormone, glucose-dependent insulinotropic polypeptide, like insulin, also directly modulates a variety of factors that are important in adipocyte homeostasis. Such factors include lipoprotein lipase, Akt, and GLUT-4, all of which promote the storage of fat. SummaryIn this review, various mechanisms by which glucose-dependent insulinotropic polypeptide may serve as a link that indirectly and directly contributes to the development of obesity will be discussed. Understanding the peptides role will potentially help provide novel ways to prevent and treat obesity.

Gastrin stabilises β -catenin protein in mouse colorectal cancer cells

As gastrin may play a role in the pathophysiology of gastrointestinal (GI) malignancies, the elucidation of the mechanisms governing gastrin-induced proliferation has recently gained considerable interest. Several studies have reported that a large percentage of colorectal tumours overexpress or stabilise the β-catenin oncoprotein. We thus sought to determine whether gastrin might regulate β-catenin expression in colorectal tumour cells. Amidated gastrin-17 (G-17), one of the major circulating forms of gastrin, not only enhanced β-catenin protein expression, but also one of its target genes, cyclin D1. Furthermore, activation of β-catenin-dependent transcription by gastrin was confirmed by an increase in LEF-1 reporter activity, as well as enhanced cyclin D1 promoter activity. Finally, G-17 prolonged the τ1/2 of β-catenin protein, demonstrating that gastrin appears to exert its mitogenic effects on colorectal tumour cells, at least in part, by stabilising β-catenin.

Gastrin peptides: Pathophysiologic role in gastrointestinal carcinogenesis

Gastrin is a gastrointestinal regulatory peptide that plays a key role in the physiologic regulation of gastric acid secretion. In addition to this important biologic property, numerous studies have documented the trophic effects of both amidated and precursor gastrin peptides on the mucosa of the gastrointestinal tract. Gastrin stimulates not only the growth of normal gastrointestinal epithelial cells but also neoplastic cells in the alimentary tract and pancreas and in extraintestinal sites. Prolonged hypergastrinemia has been found to be a significant risk factor for the development of certain gastrointestinal malignancies. These studies all have suggested a potential role for gastrin in the pathophysiology of these malignancies of the gastrointestinal tract, whereby not only elevated levels of circulating gastrin but also tumor-derived gastrin may provide a stimulus for tumor growth. This review discusses the trophic properties, concentrating on two sites in the gastrointestinal tract, the colon and esophagus. Because gastrin appears to stimulate the proliferation of gastrointestinal and other malignancies, a pharmacologic means for preventing the development of neoplastic cellular hyperproliferation could be developed by inhibiting its expression. Ultimately, gastrin receptor antagonists and the suppression of antral gastrin expression may prove beneficial in decreasing tumor growth and ultimately in preventing malignant transformation throughout the gastrointestinal tract.